Induction of caspase-dependent apoptosis by apigenin by inhibiting STAT3 signaling in HER2-overexpressing MDA-MB-453 breast cancer cells

Anticancer Res. 2014 Jun;34(6):2869-82.


Background: This study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-overexpressing MDA-MB-453 breast cancer cells.

Materials and methods: The antiproliferative effects of apigenin were examined by proliferation and MTT assays. The effect of apigenin on apoptotic molecules was determined by western blotting. RT-PCR was performed to measure mRNA levels of HIF-1α and VEGF. ELISA assay was performed to measure intracellular VEGF levels. Immunocytochemistry was performed to evaluate nuclear STAT3 level.

Results: Apigenin inhibited the proliferation of MDA-MB-453 cells. Apigenin up-regulated the levels of cleaved caspase-8 and caspase-3, and induced the cleavage of PARP. Apigenin induced extrinsic apoptosis and blocked the activation (phosphorylation) of JAK2 and STAT3. Apigenin inhibited CoCl2-induced VEGF secretion and decreased the nuclear staining of STAT3.

Conclusion: Apigenin exerts its antiproliferative activity by inhibiting STAT3 signaling. Apigenin could serve as a useful compound to prevent or treat HER2-overexpressing breast cancer.

Keywords: Breast cancer; HER2; STAT3; VEGF; apigenin; apotosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apigenin / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Female
  • Flow Cytometry
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunoenzyme Techniques
  • Phosphorylation / drug effects
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Apigenin
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Caspases